Th17 cells are a subset of T helper cells that produce IL-17A, IL-17F, and IL-22, which have been linked to several autoimmune and chronic inflammatory diseases of skin, gut, and lung, including as asthma, and chronic obstructive pulmonary disease. Th17 cells play an important role in host responses and provide protective immunity against certain, but not all, bacterial and fungal infections, through the recruitment of neutrophils. Receptor interacting protein 2 (Rip2), the adapter molecule for the intracellular peptidoglycan sensors Nod1 and Nod2, plays an important role in directing innate immune responses against various bacteria (1). In our laboratory, we have focused on the important human pathogen, Chlamydia pneumoniae (CP), which has been associated with chronic conditions such as allergic asthma, chronic lung diseases, exacerbation of chronic obstructive pulmonary disease, and the progression of other chronic inflammatory diseases such as atherosclerosis and lung cancer in smokers. We previously reported that Rip2 in alveolar macrophages played a critical role in controlling CP infection in mice, and that surviving Rip2-/- mice had a profound chronic lung inflammation (2). Further characterization of this sustained inflammation revealed enhanced fibrosis and increased foci of inducible bronchus associated lymphoid tissue (iBALTs). Unexpectedly, we found that Rip2-deficient T cells were intrinsically skewed towards Th17 and IL-17A production, revealing a novel role for Rip2 in regulating Th17 differentiation. Our preliminary studies show that under pathologic IL-1- driven Th17 differentiation conditions, Rip2-/- T-cells have enhanced Th17 differentiation and increased expression of retinoic acid-related orphan receptor alpha (RORa), an important contributor to Th17 skewing. Our data also suggests that the chronic inflammation found in Rip2 deficient mice after CP infection is a result of the intrinsic Th17 skewing defect in Rip2-/- T-cells. Given the increasing recognition of NOD/Rip2 polymorphisms associated with various chronic inflammatory diseases in humans, including asthma, we will seek to determine the functional implications of this novel Rip2-Th17 cross-talk. Based upon these key novel findings, we propose the following studies focused around the central hypothesis that Rip2 deficiency in T cells intrinsically enhances Th17 differentiation thereby inducing chronic inflammation during CP infection, and that deletion of NODs/RIP2 increases Th17 skewing and pathology through enhanced ROR? activity. To test these hypotheses, we propose the following three Specific Aims: Aim 1 is to determine the role of IL-17 production during CP infection and chronic lung inflammation. Aim 2 is to determine the role of the Rip2/IL-17 axis in C. pneumoniae infection-induced chronic lung inflammation/lung fibrosis and the role of human Rip2 SNPs in Th17 skewing. Aim 3 is to investigate the molecular mechanisms by which Rip2 regulates Th17 differentiation.